Major urinary protein 1 interacts with cannabinoid receptor type 1 in fatty acid-induced hepatic insulin resistance in a mouse hepatocyte model

Biochem Biophys Res Commun. 2015 May 15;460(4):1063-8. doi: 10.1016/j.bbrc.2015.03.155. Epub 2015 Apr 3.


Hepatic insulin resistance (HIR) is a metabolic abnormality characterized by increased gluconeogenesis which usually contributes from an elevation of free fatty acids. Cannabinoid receptor type 1 (CB1R) and major urinary protein 1 (MUP1) are thought to play pivotal roles in mitochondrial dysfunction, liver steatosis and insulin resistance. The aim of this study was to explore the role of MUP1 in CB1R-mediated HIR through the dysregulation of mitochondrial function in AML12 mouse hepatocytes challenged with high concentration of free fatty acids (HFFA). Firstly we observed that treatment of AM251, a selective CB1R antagonist, obviously reversed the HFFA-induced reduction of MUP1 protein expression both in vivo and in vitro. Additionally, our results revealed that AM251 also reverted HFFA-mediated decrease of the mRNA level of mitochondrial biogenesis-related factors, mtDNA amount, ATP production, mitochondrial respiratory complexes-I and -III, and mitochondrial membrane potential, thus consequently might correlate with a parallel reduction of ROS production. Meanwhile, AM251 attenuated HFFA-induced impairment of insulin signaling phosphorylation and elevation of phosphoenolpyrvate carboxykinase (PEPCK) and glucose 6-phosphatase (G6Pase), two key enzymes of gluconeogenesis. Silence of MUP1 gene abolished the inhibitory effect of AM251 on HFFA-mediated elevation of PEPCK and G6Pase expression, whereas the suppression of insulin signaling and mRNA level of mitochondrial biogenesis-related factors were only partially recovered. Altogether, these findings suggest that the anti-HIR effect of AM251 via improvement of mitochondrial functions might occur in a MUP1-dependent manner.

Keywords: Cannabinoid receptor type 1; Hepatic insulin resistance; Major urinary protein 1; Mitochondrial dysfunction.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blotting, Western
  • Diet, High-Fat
  • Fatty Acids / metabolism*
  • Gene Silencing
  • Hepatocytes / metabolism*
  • Insulin Resistance*
  • Liver / metabolism*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Models, Biological
  • Piperidines / pharmacology
  • Proteins / genetics
  • Proteins / metabolism*
  • Pyrazoles / pharmacology
  • Reactive Oxygen Species / metabolism
  • Real-Time Polymerase Chain Reaction
  • Receptor, Cannabinoid, CB1 / antagonists & inhibitors
  • Receptor, Cannabinoid, CB1 / metabolism*


  • Fatty Acids
  • Piperidines
  • Proteins
  • Pyrazoles
  • Reactive Oxygen Species
  • Receptor, Cannabinoid, CB1
  • major urinary proteins
  • AM 251